The subject-matter of the present invention is new unsaturated derivatives at the 4-position of 6-tert-butyl-1-1 dimethylindane, their process of preparation and their use in human or veterinary medicine and in cosmetics.
It is well known that all-trans-retinoic acid (AtRA) and certain synthetic analogues (retinoids) play a fundamental role in cell proliferation and differentiation. These pharmacological properties confer an advantage on retinoids in the treatment of dermatological conditions, such as acne or psoriasis. In addition, these compounds have applications in oncology in the treatment and prevention of certain cancers.
The compounds according to the invention, which are synthetic compounds also of the retinoid type, exhibit an activity in the fields of cell differentiation and proliferation. These compounds can consequently be used in the topical and systemic treatment of dermatological conditions linked to a disorder of keratinization, dermatological conditions (or others) having an inflammatory, viral and/or immunoallergic component, and dermal or epidermal proliferations, whether benign or malignant. These compounds can additionally be used in the treatment of degenerative diseases of the connective tissue, for controlling ageing of the skin, whether photoinduced or chronologic, and treating disorders of cicatrization. Finally, they find an application in the ophthalmological field, in particular in the treatment of corneopathies.
They can also be used in cosmetic compositions for body or hair hygiene.
The compounds according to the invention can be represented by the following general formula (I): 
in which:
X represents:
(i) either a divalent radical of following formula: 
and Y then represents a divalent radical of following formula: 
(ii) or a divalent radical of formula: 
and Y then represents either a divalent radical corresponding to the divalent radical of formula (b) above or one of the divalent radicals of following formula: 
Z being xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or 
R1 represents xe2x80x94CH3, xe2x80x94(CH2)pxe2x80x94OR4, xe2x80x94(CH2)pxe2x80x94COR5 or xe2x80x94S(O)txe2x80x94R6,
p being 0, 1 , 2 or 3,
t being 0, 1 or 2,
R2 represents H or lower alkyl,
R3 represents H, lower alkoxy or xe2x80x94OCOR7,
R4 represents H, lower alkyl, xe2x80x94COR7, aryl, aralkyl, mono- or polyhydroxyalkyl, or a polyether radical,
R5 represents H, lower alkyl, xe2x80x94OR8 or 
R6 represents H or lower alkyl,
R7 represents lower alkyl,
R8 represents H, alkyl, alkenyl, alkynyl, aryl, aralkyl, mono- or polyhydroxyalkyl, a sugar residue or an amino acid residue,
rxe2x80x2 and rxe2x80x3, identical or different, represent H, lower alkyl, xe2x80x94COR7, aryl, a sugar residue or an amino acid residue or rxe2x80x2 and rxe2x80x3, taken together form a heterocycle, and the salts of the compounds of formula (I), when R1 represents a carboxylic acid group, and the geometrical and optical isomers of the compounds of formula (I).
When the compounds according to the invention are provided in the form of a salt, it is preferably a salt of an alkali metal or alkaline earth metal or alternatively of zinc or of an organic amine.
According to the invention, lower alkyl radical is understood to mean a linear or branched C1-C6 radical, preferably methyl, ethyl, propyl, isopropyl, tert-butyl and n-hexyl radicals.
Alkyl radical is understood to mean a linear or branched C1-C20 radical, preferably methyl, ethyl, isopropyl, butyl, tert-butyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.
Lower alkoxy radical is understood to mean a radical having 1 to 6 carbon atoms, preferably methoxy, ethoxy, isopropoxy and butoxy radical.
Alkenyl radical is understood to mean a linear or branched radical preferably having from 2 to 5 carbon atoms and exhibiting one or two ethylenic unsaturation(s), such as the allyl radical.
Alkynyl radical is understood to mean a radical, having from 3 to 6 carbon atoms, comprising 1 or 2 triple bond(s), such as the 2-propynyl, 2-butynyl and 2,4-hexadiynyl radicals.
The radical of formula xe2x80x94COR7 (R7 being lower alkyl) or acyl radical is preferably selected from the acetyl, propionyl or pivaloyl radicals.
Monohydroxyalkyl radical is understood to mean a radical preferably having from 2 to 4 carbon atoms, preferably the 1-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl or 4-hydroxybutyl radicals.
Polyhydroxyalkyl radical is understood to mean a radical preferably having from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentyl radicals or the pentaerythritol residue.
Polyether radical is understood to mean a radical having from 2 to 6 carbon atoms and from 1 to 3 oxygen or sulphur atoms, such as the methoxymethyl ether, methoxyethoxymethyl ether or methylthiomethyl ether radicals.
Aryl radical is understood to mean preferably the phenyl radical, optionally substituted by at least one halogen atom, such as Br, Cl or I, one hydroxyl group, one nitro group, one methoxy group or one optionally substituted amine group.
Aralkyl radical is understood to mean preferably the benzyl or phenethyl radical, optionally substituted by at least one halogen atom as defined above, one hydroxyl group, one nitro group or one methoxy group.
Amino acid residue is understood to mean in particular a residue deriving from lysine, glycine or aspartic acid.
Sugar residue is understood to mean a residue deriving from glucose, galactose or mannose or alternatively glucuronic acid.
Heterocycle is understood to mean preferably a piperidino, morpholino, pyrrolidino or piperazino radical, the latter being optionally substituted in the 4-position by a lower C1-C6 alkyl or a mono- or polyhydroxyalkyl as defined above.
According to a first preferred embodiment, the compounds according to the invention correspond to the following general formula: 
in which:
Y1 represents one of the divalent radicals of formula: 
R2, R3 and Z having the same meanings as those given for the formula (I) above,
Rxe2x80x21 represents xe2x80x94(CH2)pxe2x80x2xe2x80x94COORxe2x80x28, pxe2x80x2 being 0 and Rxe2x80x28 representing H or lower alkyl.
According to a second preferred embodiment, the compounds according to the invention correspond to the following general formula: 
in which:
R2 represents H or lower alkyl, and
Rxe2x80x21 represents xe2x80x94(CH2)pxe2x80x2xe2x80x94COORxe2x80x28, pxe2x80x2 being 0 and Rxe2x80x28 being H or lower alkyl.
Among the compounds corresponding to the above formulae (I), (II) and (III), mention may be made of the following examples:
methyl (2E,4E)-6-[4-(6-tert-butyl-1,1-dimethylindanyl)]-3-methylhepta-2,4,6-trienoate,
(2E,4E)-6-[4-(6-tert-butyl-1,1-dimethylindanyl)]-3-methylhepta-2,4,6-trienoic acid,
methyl (2E,4E)-6-[4-(6-tert-butyl-1,1-dimethylindanyl)]hepta-2,4,6-trienoate,
(2E,4E)-6-[4-(6-tert-butyl-1,1-dimethylindanyl)]hepta-2,4,6-trienoic acid,
methyl (2E,4E,6E)-7-[4-(6-tert-butyl-1,1-dimethylindanyl)]-3,7-dimethylhepta-2,4,6-trienoate,
(2E,4E,6E)-7-[4-(6-tert-butyl-1,1-dimethylindanyl)]-3,7-dimethylhepta-2,4,6-trienoic acid,
methyl (2E,4E,6E)-7-[4-(6-tert-butyl-1,1-dimethylindanyl)]-7-methylhepta-2,4,6-trienoate,
(2E,4E,6E)-7-[4-(6-tert-butyl-1,1-dimethylindanyl)]-7-methylhepta-2,4,6-trienoic acid,
ethyl 4-[1-[4-(6-tert-butyl-1,1-dimethylindanyl)]ethenyl]benzoate,
4-[1-[4-(6-tert-butyl-1,1-dimethylindanyl)]ethenyl]benzoic acid,
3-[1-(6-tert-butyl-1,1-dimethylindan-4yl)ethen-1-yl]-thiophene-2carboxylic acid,
3-[1-(6-tert-butyl-1,1-dimethylindan-4-yl)ethen-1-yl]-thiophene-2-carboxaldehyde,
2-[1-(6-tert-butyl-1,1-dimethylindan-4-yl)ethen-1-yl]-thiophene-3-carboxaldehyde,
2-[1-(6-tert-butyl-1,1-dimethylindan-4-yl)ethen-1-yl]-thiophene-3-carboxylic acid,
Methyl 6-[(6-tert-butyl-1,1-dimethylindan-4-yl)ethen-1-yl]-3-pyridinecarboxylate,
6-[(6-tert-butyl-1,1-dimethylindan-4-yl)ethen-1-yl]-3-pyridinecarboxylic acid.
The present invention is also directed to the process for the preparation of the compounds of formula (I) according to the reaction schemes of Tables A and B.
With reference to Table A, 4-acetyl-6-tert-butyl-1,1-dimethylindane (1) is converted into the intermediate 6-tert-butyl-4-ethenyl-1,1-dimethylindane by treatment with lithium diisopropylamide (LDA) and is then treated with an alkyl chlorophosphate, such as diethyl chlorophosphate. The resulting mixed phosphate intermediate is subsequently again treated with LDA and thus results in the 6-tert-butyl-4-ethynyl-1,1-dimethylindane (2).
The latter can then be converted to the vinyl iodide (3) by the action of trimethylsilyl iodide or chloride or be converted to the propylene iodide (4) by a methylalumination mediated by a zirconium complex (bis(cyclopentadienyl)zirconium dichloride complex), followed by an exchange between aluminum and iodine according to the conditions described by A. Tollado et al., Tetrahedron, 1995, vol. 5, pages 2435-2454.
The iodinated derivatives (3) and (4) are subsequently used in a crosscoupling reaction with a polyenic organostannic compound of formula (5), catalyzed by palladium (tris(dibenzylideneacetone) palladium complex), in order to result in the compounds of the formulae (Ia) and (Ib). The organostannic compound (5) can be replaced by a polyenic boronic acid and, in this case, the reaction is carried out under the crosscoupling conditions of the Suzuki type, modified by Kishi. According to these conditions, the mixture contains thallium hydroxide and the catalyst is Pd(PPh3)4, these conditions being described in detail in Synthesis, 1995, No. 3, p. 285.
With reference now to Table B, the compounds of formula (Ic) can be obtained from the vinyl iodide (3) of Table A by condensation with an arylboronic derivative (6) in the presence of tetrakis(triphenylphosphine)-palladium according to conditions described above in Synthesis.
When R1 represents xe2x80x94COOH in the compounds according to the invention, these compounds are prepared by protecting the carboxylic acid group with a protective group of alkyl, allyl or tert-butyl type.
Conversion to the free form can be carried out:
in the case of an alkyl protective group, by means of sodium hydroxide or lithium hydroxide in an alcoholic solvent, such as methanol, or in THF;
in the case of an allyl protective group, by means of a catalyst, such as certain transition metal complexes, in the presence of a secondary amine, such as morpholine;
in the case of a protective group of tert-butyl type, by means of trimethylsilyl iodide.
When R1 represents xe2x80x94OH in the compounds according to the invention, these compounds can be obtained from the corresponding acid by reduction in the presence of lithium aluminum hydride.
When R1 represents 
the compounds can be obtained by conversion of the corresponding acid to the acid chloride, for example with thionyl chloride, and then reaction with ammonia or an appropriate amine.
The compounds according to the invention bind to RXR receptors and have an agonist activity with respect to these receptors.
The binding and transactivation properties as RXR agonists are determined by known methods, such as, for example, according to Levin et al., Nature, 1992, 355, 359-361; Allenby et al., Proc. Natl. Acad. Sci., 1993, 90, 30-4; Allenby et al., J. Biol. Chem., 1994, 269, 16689-1669.
The RXR agonist activity is also determined by the test as disclosed in EP-A-749,752. This test comprises the following steps:
(i) a sufficient amount of a compound which is an active ligand of at least one receptor of the superfamily of steroid/thyroid nuclear receptors, other than a ligand specific or RXR receptors, and which can heterodimerize with the RXRs, such as, for example, an RAR agonist molecule, is applied topically to a portion of the skin of a mammal,
(ii) a molecule capable of exhibiting an agonist activity with respect to RXRs is administered systemically or topically to the same portion of the skin of a mammal, before, during or after the steps (i),
(iii) the pharmacological response over the portion of the skin, thus treated, of the mammal is then evaluated. This response consists of a thickening of the ear. Thus, the response of a topical application to the ear of a mammal of an RAR agonist will be potentiated by topical or systemic administration of an agonist for RXR receptors.
The present invention is also directed to the above compounds of formula (I) as medicament.
The compounds according to the invention are particularly well suited to the following fields of treatment:
1) For treating dermatological conditions linked to a disorder of keratinization involving differentiation and proliferation, in particular for treating acne vulgaris, comedonic or polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acnes such as solar drug-induced or occupational acne,
2) For treating other types of disorders of keratinization, in particular ichthyoses, ichthyosiform conditions, Darier""s disease, palmoplantar keratoderma, leucoplakia and leucoplakiform conditions or cutaneous or mucosal (oral) lichen,
3) For treating other dermatological conditions linked to a disorder of keratinization with an inflammatory and/or immunoallergic component and, in particular, all forms of psoriasis, either cutaneous, mucosal or ungual, and even psoriatic rheumatism, or alternatively cutaneous atopy, such as eczema, or respiratory atopy or alternatively gingival hypertrophy; the compounds can also be used in certain inflammatory conditions which do not show disorders of keratinization,
4) For treating all dermal or epidermal proliferations, whether they are benign or malignant and whether they are or are not of viral origin, such as common warts, flat warts and epidermodysplasia verruciformis, florid or oral papillomatoses and the proliferations, which can be induced by ultraviolet radiation, in particular in the case of basal cell and prickle cell epithelioma,
5) For treating other dermatological disorders, such as bullous dermatoses and collagen diseases,
6) For treating certain ophthalmological disorders, in particular corneopathies,
7) For repairing or controlling ageing of the skin, whether photoinduced or chronologic, or for reducing actinic keratoses and pigmentations or any pathology associated with chronologic or actinic ageing,
8) For preventing or treating the stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy,
9) For preventing or treating disorders of cicatrization or for preventing or repairing stretch marks,
10) For controlling disorders of the sebaceous function such as hyperseborrhoea of acne or simple seborrhoea,
11) In the treatment or prevention of cancerous or precancerous conditions,
12) In the treatment of inflammatory conditions such as arthritis,
13) In the treatment of any condition of viral origin at the cutaneous or general level,
14) In the prevention or treatment of alopecia,
15) In the treatment of dermatological or general conditions with an immunological component,
16) In the treatment of ailments of the cardiovascular system such as arteriosclerosis, hypertension, non-insulin-dependent diabetes and obesity.
In the therapeutic fields mentioned above, the compounds according to the invention can advantageously be employed in combination with other known retinoids, with vitamins D or their derivatives, with corticosteroids or oestrogens, or employed in combination with compounds which control free radicals, with xcex1-hydroxy or xcex1-keto acids or their derivatives, or alternatively with potassium-channel blockers.
Vitamins D or their derivatives is understood to mean, for example, the derivatives of vitamin D2 or D3 and in particular 1,25-dihydroxyvitamin D3.
Compounds which control free radicals is understood to mean, for example, xcex1-tocopherol, superoxide dismutase (SOD), ubiquinol or certain metal-chelating agents.
xcex1-Hydroxy or a-keto acids or their derivatives is understood to mean, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids and salicylic acid derivatives or their salts, amides or esters.
Potassium-channel blockers is understood to mean, for example, minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives.
It is also a subject-matter of the present invention a medicinal composition comprising at least one compound of formula (I) as defined hereinabove, one of its optical or geometrical isomers or one of its salts.
The medicinal compositions are more particularly intended especially for treating the abovementioned conditions and are characterized in that they comprise, in a pharmaceutically acceptable vehicle, at least one compound of formula (I), one of its optical or geometrical isomers or one of its salts.
The administration of the compounds according to the invention can be carried out enterally, parenterally, topically or ocularly.
For enteral administration, the medicaments can be provided in the form of tablets, hard gelatin capsules, dragxc3xa9es, syrups, suspensions, solutions, powders, granules, emulsions or polymeric or lipid vesicles or nanospheres or microspheres which make possible controlled release. For parenteral administration, the compositions can be provided in the form of solutions or suspensions for infusion or for injection.
The compounds according to the invention are generally administered at a daily dose of approximately 0.01 mg/kg to 100 mg/kg by body weight in 1 to 3 intakes.
The topical pharmaceutical compositions containing the compounds according to the invention are intended for treating the skin and the mucosal membranes and are provided in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be provided in the form of polymeric or lipid vesicles or nanospheres or microspheres or of polymeric patches and of hydrogels which make possible controlled release. These compositions for topical administration can be provided either in anhydrous form or in aqueous form, according to the clinical indication.
For ocular administration, they are mainly eye washes.
The compositions for topical or ocular administration contain at least one compound of formula (I) as defined above, one of its optical or geometrical isomers or one of its salts, at a concentration preferably of between 0.001 and 5% with respect to the total weight of the composition.
The compounds of formula (I) according to the invention also find an application in the cosmetics field, in particular in body and hair hygiene, and especially for the treatment of skin with a tendency to develop acne, for hair regrowth and combating hair loss, for combating the greasy appearance of the skin or the hair, protecting against the deleterious effects of sunlight or in the treatment of physiologically dry skin, and for preventing and/or for controlling photoinduced or chronologic ageing.
In the cosmetics field, just as in the therapeutic field, the compounds according to the invention can advantageously be employed in combination with other known retinoids, with vitamins D or their derivatives, or with corticosteroids, or alternatively in combination with compounds which control free radicals, with xcex1-hydroxy or xcex1-keto acids or their derivatives, or alternatively with potassium-channel blockers.
The cosmetic compositions according to the present invention comprise, in a cosmetically acceptable vehicle, at least one compound of formula (I), one of its optical or geometrical isomers or one of its salts, these compositions being provided in particular in the form of a cream, a milk, a lotion, a gel, polymeric or lipid vesicles or nanospheres or microspheres, a soap or a shampoo.
The concentration of compound of formula (I) in the cosmetic compositions is preferably between 0.001 and 3% by weight.
The pharmaceutical and cosmetic compositions according to the invention can additionally contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives and especially: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; hydrating agents such as glycerol, polyethylene glycol 400, thiamorpholinone and its derivatives or urea; anti-seborrhoeic or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts and their derivatives, or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, or tetracyclins; antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolinones; agents promoting hair regrowth, such as minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives, diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and phenytoin (5,4-diphenylimidazolidine-2,4-dione); non-steroidal anti-inflammatory agents; is carotenoids and especially xcex2-carotene; anti-psoriatic agents such as anthralin and its derivatives; and finally eicosa-5,8,11,14-tetraynoic and eicosa-5,8,11-triynoic acids, their esters and amides.
The compositions according to the invention can also contain flavour enhancers, preserving agents such as the esters of para-hydroxybenzoic acid, stabilizing agents, moisture-regulating agents, pH-regulating agents, osmotic-pressure-modifying agents, emulsifying agents, UV-A and UV-B screening agents and antioxidants such as xcex1-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene.
A number of examples of the preparation of active compounds of formula (I) according to the invention, as well as formulation examples comprising them, will now be given by way of illustration.